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1. GLP-1 Receptor Agonists

Overview

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injectable drugs that improve blood sugar control and have beneficial effects on weight. They mimic the action of the naturally occurring hormone GLP-1, which is involved in blood sugar regulation.

How They Work

GLP-1 receptor agonists work by enhancing the body’s natural ability to lower blood sugar levels. They increase insulin secretion in response to meals, decrease glucagon production (a hormone that raises blood sugar), and slow the emptying of the stomach, which helps in reducing appetite and potentially leading to weight loss.

Common Medications

• Exenatide (Byetta): Administered twice daily.
• Liraglutide (Victoza): A once-daily injection.
• Dulaglutide (Trulicity): Requires a once-weekly injection.
• Semaglutide (Ozempic): Also taken weekly.

Exenatide (Byetta)

Dosage and Administration

Exenatide is administered as a subcutaneous injection. The starting dose is typically 5 micrograms injected twice a day, 30 minutes before the first and last meal of the day. If well-tolerated, after a month, the dose can be increased to 10 micrograms twice daily for better glycemic control.

Side Effects

The most common side effects include mild to moderate nausea, which decreases over time. Other side effects may include vomiting, diarrhea, dizziness, headache, and a feeling of jitteriness. More serious, but less common, side effects include severe pancreatitis, renal impairment, and hypersensitivity reactions.

Recommendations and Contraindications

Exenatide is recommended for type 2 diabetes patients who are not achieving desired glucose control with oral medication alone and is particularly effective in overweight or obese patients due to its potential weight-loss benefits. It is contraindicated in patients with severe renal impairment or a history of severe gastrointestinal disease.

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Liraglutide (Victoza)

Dosage and Administration

Liraglutide is given once daily at any time, independent of meals. The initial dose is 0.6 mg per day for one week, primarily to reduce gastrointestinal symptoms, then increased to 1.2 mg. If further glycemic control is needed, the dose may be increased to a maximum of 1.8 mg daily.

Side Effects

Common side effects include nausea, diarrhea, and vomiting. Liraglutide may also increase the risk of thyroid C-cell tumors, based on animal studies, hence it carries a boxed warning regarding thyroid C-cell tumor risk. It can also cause pancreatitis, and should not be used in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Recommendations and Contraindications

Liraglutide is effective in lowering blood glucose and body weight and may be particularly beneficial for cardiovascular health, as it has been shown to reduce the risk of cardiovascular events in people with type 2 diabetes. It is contraindicated in patients with a personal or family history of certain thyroid cancers.

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Dulaglutide (Trulicity)

Dosage and Administration

Dulaglutide is administered once a week, at any time of day, with or without meals. It is available in doses of 0.75 mg and 1.5 mg in an auto-injector pen for easier administration. Patients may start with 0.75 mg and increase to 1.5 mg for additional glycemic control as tolerated.

Side Effects

Side effects include nausea, diarrhea, vomiting, abdominal pain, and decreased appetite. Serious but rare side effects include severe gastrointestinal disease, pancreatitis, and the potential risk of thyroid C-cell tumors.

Recommendations and Contraindications

Dulaglutide is recommended for individuals with type 2 diabetes, especially those who require a convenient dosing schedule and are also seeking potential cardiovascular benefits. It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients who have had a hypersensitive reaction to the drug.

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Semaglutide (Ozempic)

Dosage and Administration

Semaglutide is injected once a week, on the same day each week, at any time of day, with or without meals. The starting dose is 0.25 mg per week for four weeks, increasing to 0.5 mg per week for glycemic control, with a further increase to 1 mg if additional control is needed.

Side Effects

Common side effects include nausea, vomiting, stomach pain, diarrhea, and constipation. Like other GLP-1 receptor agonists, semaglutide may increase the risk of pancreatitis, and it carries warnings about the potential risk of thyroid C-cell tumors.

Recommendations and Contraindications

Semaglutide is effective for improving glycemic control and promoting significant weight loss. It is also indicated to reduce the risk of major cardiovascular events such as heart attack, stroke, or death in adults with type 2 diabetes and known heart disease. It should not be used in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Tirzepatide (Mounjaro)

Overview

Tirzepatide is unique as it not only acts as a GLP-1 receptor agonist but also mimics the effects of glucose-dependent insulinotropic polypeptide (GIP), another incretin hormone that plays a role in insulin secretion and energy metabolism. This dual action makes tirzepatide particularly effective for both glycemic control and weight loss.

Dosage and Administration

Tirzepatide is administered once weekly via subcutaneous injection. The starting dose is usually 2.5 mg per week, which can be escalated over time to 5 mg, 10 mg, or up to 15 mg depending on the patient’s response and tolerability.

Side Effects

Common side effects of tirzepatide include gastrointestinal symptoms such as nausea, diarrhea, vomiting, and constipation. It may also cause reduced appetite, which contributes to weight loss. As with other GLP-1 receptor agonists, there are concerns about potential risks of thyroid C-cell tumors and pancreatitis.

Recommendations and Contraindications

Tirzepatide is recommended for individuals with type 2 diabetes, particularly those who also need to manage their weight. Due to its effects on gastric emptying, it should be used with caution in patients with gastrointestinal disorders. Like other GLP-1 receptor agonists, it should not be used in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

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General Notes on GLP-1 Receptor Agonists

Recommendations and Contraindications

These drugs are particularly recommended for individuals with type 2 diabetes who are struggling to control their blood glucose levels and who are overweight or obese. They are contraindicated in patients with a personal or family history of medullary thyroid cancer and should be used cautiously in those with a history of pancreatitis.

Additional Information

Recent studies suggest that GLP-1 receptor agonists can reduce cardiovascular events in patients with type 2 diabetes who have established cardiovascular diseases. They are often preferred due to their positive effects on weight and cardiovascular risk reduction.

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2. Amylin Analogues

Pramlintide (Symlin)

Overview

Pramlintide is a synthetic form of amylin, a hormone that is naturally secreted by the pancreas alongside insulin. Amylin plays a crucial role in regulating blood glucose levels by helping to control the rate of gastric emptying, reducing the postprandial glucagon secretion, and promoting satiety. In people with diabetes, especially those who use insulin, the production of amylin is impaired, which contributes to postprandial blood glucose spikes.

Dosage and Administration

Pramlintide is administered via subcutaneous injection immediately before major meals (those containing at least 250 calories or 30 grams of carbohydrates). The dosing regimen varies based on the type of diabetes:

• Type 1 diabetes: Start with 15 mcg per meal and titrate up to a maximum of 60 mcg as tolerated to minimize the risk of hypoglycemia.
• Type 2 diabetes: Initial dosing is 60 mcg per meal, which can be increased to 120 mcg if no significant nausea occurs.

Patients are advised to lower their mealtime insulin doses by 50% when initiating pramlintide to reduce the risk of hypoglycemia.

Side Effects

The most common side effect of pramlintide is nausea, which tends to decrease over time with continued use. Other potential side effects include:

• Anorexia
• Vomiting
• Abdominal pain
• Headache

The primary safety concern with pramlintide is hypoglycemia, particularly in type 1 diabetes. This risk is increased when pramlintide is used in combination with insulin, and it can occur immediately after meals due to delayed gastric emptying.

Recommendations and Contraindications

Pramlintide is recommended for patients with type 1 or type 2 diabetes who are already using insulin therapy but continue to experience significant fluctuations in their blood glucose levels, particularly postprandial spikes. It is particularly beneficial for those who are struggling with weight management, as it can promote weight loss due to increased satiety.

Contraindications for pramlintide use include:

• Patients with gastroparesis or other forms of impaired gastric emptying, as pramlintide can further slow gastric emptying.
• Patients with hypoglycemia unawareness, as the risk of unrecognized and therefore untreated hypoglycemia increases.
• Patients who cannot reliably monitor their blood glucose or adjust their insulin dosage on their own.

Additional Considerations

• Injection technique and timing: Proper injection technique and timing are crucial for the effectiveness of pramlintide. Injections should be given subcutaneously in the abdomen or thigh, and not in the same site as insulin to avoid mixing.
• Education on hypoglycemia management: Due to the increased risk of hypoglycemia, particularly in type 1 diabetes, patients should be thoroughly educated on how to recognize and manage hypoglycemia.
• Regular monitoring: Regular follow-up and monitoring of blood glucose levels are essential to adjust the dose of both pramlintide and insulin, especially during the initial phase of therapy.

Pramlintide represents a unique approach in diabetes treatment, addressing postprandial glucose spikes and aiding in weight management. However, its use requires careful patient selection and education to ensure safety and efficacy.

Additional Information

Patients using pramlintide have reported improved blood sugar control and weight loss, making it a valuable addition to diabetes management for suitable candidates.

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3. Injectable Combination Therapies

Injectable combination therapies for diabetes have revolutionized the management of type 2 diabetes by combining the effects of different classes of medication into a single injection. These therapies simplify the treatment regimen, potentially improving patient adherence and overall treatment outcomes.

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How They Work

Injectable combination therapies typically merge a GLP-1 receptor agonist with a basal insulin. This combination leverages the GLP-1 receptor agonist’s ability to enhance glucose-dependent insulin secretion, suppress inappropriate glucagon secretion, slow gastric emptying, and reduce appetite. At the same time, the basal insulin component provides a constant level of insulin to manage blood glucose levels throughout the day and night, particularly covering fasting periods.

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Common Medications

Xultophy (Insulin Degludec/Liraglutide)

Dosage and Administration Xultophy is administered as a once-daily injection, which can be taken at any time of the day with or without meals but should be at the same time each day. The starting dose is typically 16 units, with each unit providing 1 unit of insulin degludec and 0.036 mg of liraglutide. The dose can be adjusted based on the patient’s metabolic needs but should not exceed 50 units per day.

Side Effects Common side effects include hypoglycemia, nausea, diarrhea, and headache. As with other GLP-1 receptor agonists, there is a potential risk of thyroid C-cell tumors, and pancreatitis is a noted risk as well.

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Soliqua (Insulin Glargine/Lixisenatide)

Dosage and Administration Soliqua is injected once daily within one hour before the first meal of the day. It comes in two strengths: 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide, and 100 units/mL of insulin glargine and 50 mcg/mL of lixisenatide. The starting dose is usually 15 units (15 units of insulin glargine and 5 mcg of lixisenatide) and can be titrated up based on blood glucose response, with a maximum dose of 60 units per day.

Side Effects Side effects commonly include hypoglycemia, nausea, nasal congestion, upper respiratory tract infection, and headache. Due to its content of lixisenatide, it also carries risks similar to those of other GLP-1 receptor agonists, such as potential gastrointestinal effects and risk of pancreatitis.

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Recommendations and Contraindications

These combination therapies are particularly suited for patients with type 2 diabetes who are struggling to achieve target glucose levels with oral medication alone or who require both a GLP-1 receptor agonist and insulin but prefer to avoid multiple daily injections.

Contraindications for these therapies include:

• History of medullary thyroid carcinoma or a family history of multiple endocrine neoplasia syndrome type 2 (due to the GLP-1 component).
• Hypersensitivity to any active ingredient in the formulations.
• Patients with acute pancreatitis or a history of pancreatitis should use these medications cautiously.

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Additional Considerations

• Patient Education: Patients should be educated on the correct administration techniques, potential side effects, and the importance of adherence to the prescribed treatment regimen.
• Monitoring and Follow-Up: Regular monitoring of blood glucose levels, hemoglobin A1c, and overall health status is crucial to ensure the effectiveness of the therapy and to adjust dosages as necessary.
• Lifestyle Adjustments: Patients should also be counseled on the importance of diet and exercise as part of their diabetes management plan.

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Injectable combination therapies offer a promising solution for comprehensive diabetes management, blending the benefits of basal insulin with the potent effects of a GLP-1 receptor agonist in a single daily injection. This approach not only simplifies the regimen but also enhances the efficacy of treatment, making significant strides toward better patient outcomes in diabetes care.